What are the known genetic causes of hypertension and their management?

Known Genetic Causes of Hypertension and Their Management

Several rare monogenic forms of hypertension have been identified, accounting for approximately 3.5% of blood pressure variability, with specific genetic mutations dictating targeted treatment approaches based on the underlying pathophysiological mechanism. 1

Monogenic Forms of Hypertension

1. Glucocorticoid-Remediable Aldosteronism (GRA)

• Pathophysiology: Chimeric gene duplication between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) genes, causing ectopic aldosterone production under ACTH regulation 2
• Clinical features: Early-onset hypertension, often in childhood; family history; may have hypokalemia
• Diagnosis: Genetic testing for the chimeric gene; suppressed plasma renin activity with elevated aldosterone levels
• Management: Glucocorticoid therapy (dexamethasone or prednisone) to suppress ACTH; alternatively, mineralocorticoid receptor antagonists 2

2. Liddle Syndrome

• Pathophysiology: Activating mutations in the epithelial sodium channel (ENaC) genes (SCNN1B, SCNN1G) causing increased sodium reabsorption 1
• Clinical features: Early-onset hypertension, hypokalemia, metabolic alkalosis, suppressed renin and aldosterone levels
• Diagnosis: Genetic testing; biochemical profile showing low renin and aldosterone
• Management: Amiloride or triamterene (ENaC blockers); avoid spironolactone (ineffective) 1

3. Apparent Mineralocorticoid Excess (AME)

• Pathophysiology: Mutations in HSD11B2 gene (11β-hydroxysteroid dehydrogenase type 2), allowing cortisol to activate mineralocorticoid receptors 1
• Clinical features: Severe hypertension, hypokalemia, metabolic alkalosis, low renin and aldosterone
• Diagnosis: Elevated cortisol-to-cortisone ratio in urine; genetic testing
• Management: Spironolactone, eplerenone, or amiloride; low-sodium diet 1

4. Pseudohypoaldosteronism Type II (Gordon Syndrome)

• Pathophysiology: Mutations in WNK kinases or KLHL3/CUL3 genes, increasing sodium chloride cotransporter activity 1
• Clinical features: Hypertension, hyperkalemia, metabolic acidosis, normal renal function
• Diagnosis: Biochemical profile; genetic testing
• Management: Thiazide diuretics (specifically target the pathophysiology) 1

5. Primary Aldosteronism (Familial Hyperaldosteronism Types I-IV)

• Pathophysiology: Various germline mutations in ion channels (KCNJ5, CACNA1D, CACNA1H) and chloride channels (CLCN2) 3
• Clinical features: Hypertension, variable hypokalemia, suppressed renin, elevated aldosterone
• Diagnosis: Elevated aldosterone-to-renin ratio; confirmatory testing; genetic analysis
• Management: Mineralocorticoid receptor antagonists; surgical adrenalectomy for unilateral disease 1, 3

6. Congenital Adrenal Hyperplasia

• Pathophysiology: Deficiencies in cortisol synthesis enzymes (commonly 21-hydroxylase) 4
• Clinical features: Hypertension, virilization in females, salt wasting or salt retention
• Diagnosis: Elevated 17-hydroxyprogesterone; genetic testing
• Management: Glucocorticoid replacement; mineralocorticoid antagonists if hypertensive 4

Diagnostic Approach

1. Consider genetic testing when:

   • Early-onset hypertension (before age 30) 1
   • Family history of early-onset hypertension
   • Resistant hypertension
   • Hypokalemia or hyperkalemia
   • Abnormal renin-aldosterone profile

2. Initial evaluation:

   • Measure serum electrolytes, particularly potassium
   • Plasma renin activity and aldosterone levels
   • Aldosterone-to-renin ratio
   • 24-hour urinary free cortisol (if Cushing's suspected)

3. Confirmatory testing:

   • Specific genetic testing based on biochemical profile
   • Fludrocortisone suppression test for primary aldosteronism 1
   • Adrenal imaging if adenoma suspected

Management Principles

• Target therapy to specific mechanism: Each genetic form requires specific treatment targeting the underlying pathophysiology
• Avoid ineffective medications: Standard antihypertensives may be ineffective in monogenic forms
• Monitor electrolytes: Regular monitoring of potassium and other electrolytes is essential
• Family screening: Consider screening family members once a genetic diagnosis is made

Clinical Pearls and Pitfalls

• Don't miss the diagnosis: Consider genetic causes in resistant hypertension or early-onset hypertension
• Inappropriate therapy: Using standard antihypertensives without addressing the underlying mechanism may result in poor control
• Medication interactions: Be aware of potential interactions between specific treatments and other medications
• Pregnancy considerations: Special attention needed for women with genetic hypertension during pregnancy
• Long-term follow-up: Regular monitoring for end-organ damage is essential

While monogenic forms of hypertension are rare, accounting for only a small percentage of all hypertension cases, their identification is crucial as they often respond to specific targeted therapies rather than conventional antihypertensive approaches.